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Project description:The incidence of Alzheimer's disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths1, the latter of which is associated with secondary neuroinflammation2,3. As oligodendrocytes support axonal energy metabolism and neuronal health4-7, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote Aβ plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD.
| S-EPMC10247380 | biostudies-literature
Project description:Ageing-associated myelin dysfunction drives amyloid deposition in mouse models of Alzheimer's disease
| PRJNA738456 | ENA
Project description:Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.
| S-EPMC4196723 | biostudies-literature
Project description:Alzheimer's disease begins about two decades before the onset of symptoms or neuron death, and is believed to be caused by pathogenic amyloid-? aggregates that initiate a cascade of molecular events culminating in widespread neurodegeneration. The microtubule binding protein tau may mediate the effects of amyloid-? in this cascade. Amyloid plaques comprised of insoluble, fibrillar amyloid-? aggregates are the most characteristic feature of Alzheimer's disease. However, the correspondence between the distribution of plaques and the pattern of neurodegeneration is tenuous. This discrepancy has stimulated the investigation of other amyloid-? aggregates, including soluble amyloid-? oligomers. Different soluble amyloid-? oligomers have been studied in several mouse models, but not systematically in humans. Here, we measured three amyloid-? oligomers previously described in mouse models-amyloid-? trimers, A?*56 and amyloid-? dimers-in brain tissue from 75 cognitively intact individuals, ranging from young children to the elderly, and 58 impaired subjects with mild cognitive impairment or probable Alzheimer's disease. As in mouse models, where amyloid-? trimers appear to be the fundamental amyloid-? assembly unit of A?*56 and are present in young mice prior to memory decline, amyloid-? trimers in humans were present in children and adolescents; their levels rose gradually with age and were significantly above baseline in subjects in their 70s. A?*56 levels were negligible in children and young adults, rose significantly above baseline in subjects in their 40s and increased steadily thereafter. Amyloid-? dimers were undetectable until subjects were in their 60s; their levels then increased sharply and correlated with plaque load. Remarkably, in cognitively intact individuals we found strong positive correlations between A?*56 and two pathological forms of soluble tau (tau-CP13 and tau-Alz50), and negative correlations between A?*56 and two postsynaptic proteins (drebrin and fyn kinase), but none between amyloid-? dimers or amyloid-? trimers and tau or synaptic proteins. Comparing impaired with age-matched unimpaired subjects, we found the highest levels of amyloid-? dimers, but the lowest levels of A?*56 and amyloid-? trimers, in subjects with probable Alzheimer's disease. In conclusion, in cognitively normal adults A?*56 increased ahead of amyloid-? dimers or amyloid-? trimers, and pathological tau proteins and postsynaptic proteins correlated with A?*56, but not amyloid-? dimers or amyloid-? trimers. We propose that A?*56 may play a pathogenic role very early in the pathogenesis of Alzheimer's disease.
| S-EPMC3634198 | biostudies-other
Project description:Amyloid beta (Aβ) peptides impair multiple cellular pathways and play a causative role in Alzheimer's disease (AD) pathology, but how the brain proteome is remodeled by this process is unknown. To identify protein networks associated with AD-like pathology, we performed global quantitative proteomic analysis in three mouse models at young and old ages. Our analysis revealed a robust increase in Apolipoprotein E (ApoE) levels in nearly all brain regions with increased Aβ levels. Taken together with prior findings on ApoE driving Aβ accumulation, this analysis points to a pathological dysregulation of the ApoE-Aβ axis. We also found dysregulation of protein networks involved in excitatory synaptic transmission. Analysis of the AMPA receptor (AMPAR) complex revealed specific loss of TARPγ-2, a key AMPAR-trafficking protein. Expression of TARPγ-2 in hAPP transgenic mice restored AMPA currents. This proteomic database represents a resource for the identification of protein alterations responsible for AD.
| S-EPMC5726791 | biostudies-literature
Project description:The purpose of this project was to compare whole genome expression in 5 transgenic mice that show either amyloid plaques or tangle pathology to the expression in wild-type control mice at different stages of disease progression (2, 4, 8 or 18 months of age). Mouse genes with expression correlating to pathology were then compared to human genes showing DNA variation in human population associated with dementia (from GWAS).
2019-10-31 | GSE137313 | GEO
Project description:INTRODUCTION:The objective of this study was to evaluate amyloid ? (A?) deposition patterns in different groups of cerebral ? amyloidosis: (1) nondemented with amyloid precursor protein overproduction (Down syndrome); (2) nondemented with abnormal processing of amyloid precursor protein (preclinical autosomal dominant Alzheimer disease); (3) presumed alteration in A? clearance with clinical symptoms (late-onset AD); and (4) presumed alterations in A? clearance (preclinical AD). METHODS:We performed whole-brain voxelwise comparison of cerebral A? between 23 Down syndrome, 10 preclinical autosomal dominant Alzheimer disease, 17 late-onset AD, and 16 preclinical AD subjects, using Pittsburgh Compound B-positron emission tomography. RESULTS:We found both Down syndrome and preclinical autosomal dominant Alzheimer disease shared a distinct pattern of increased bilateral striatal and thalamic A? deposition compared to late-onset AD and preclinical AD. CONCLUSION:Disorders associated with early-life alterations in amyloid precursor protein production or processing are associated with a distinct pattern of early striatal fibrillary A? deposition before significant cognitive impairment. A better understanding of this unique pattern could identify important mechanisms of A? deposition and possibly important targets for early intervention.
| S-EPMC5994364 | biostudies-literature
Project description:IntroductionThe typical spatial pattern of amyloid-β (Aβ) in diagnosed Alzheimer's disease (AD) is that of a symmetrical hemispheric distribution. However, Aβ may be asymmetrically distributed in early stages of AD. Aβ distribution on PET has previously been explored in MCI and AD, but it has yet to be directly investigated in preclinical AD (pAD). We examined how Aβ was distributed in individuals with pAD and MCI using 11C-Pittsburgh Compound B (PiB) PET.MethodsIn this PET study, 79 subjects were retrospectively enrolled, including 34 controls, 24 pAD, and 21 MCI. All subjects underwent APOE genotyping, 11C-PiB PET, MRI, and cognitive testing. We explored differences in Aβ load, Aβ lateralisation, and Aβ distribution, as well as associations between Aβ distribution and cognition.ResultsThe Aβ asymmetry index (AI) differed between groups, with pAD having the highest Aβ AI as compared to both controls and MCI. There was no clear Aβ lateralisation in pAD, but there was a non-significant trend towards Aβ being more left-lateralised in MCI. There were no correlations between the cognitive scores and Aβ AI or Aβ lateralisation in pAD or MCI.ConclusionThe distribution of Aβ is most asymmetrical in pAD, as Aβ first starts accumulating, and it then becomes less asymmetrical in MCI, when Aβ has spread further, suggesting that more pronounced asymmetrical Aβ distribution may be a distinguishing factor in pAD. Longitudinal studies examining the distribution of Aβ across the AD continuum are needed.
| S-EPMC9997142 | biostudies-literature
Project description:The relationship between amyloid-? (A?) species and tau pathology in Alzheimer's disease (AD) is not fully understood. Here, we provide direct evidence that A?42/40 ratio, not total A? level, plays a critical role in inducing neurofibrillary tangles (NTFs) in human neurons. Using 3D-differentiated clonal human neural progenitor cells (hNPCs) expressing varying levels of amyloid ? precursor protein (APP) and presenilin 1 (PS1) with AD mutations, we show that pathogenic tau accumulation and aggregation are tightly correlated with A?42/40 ratio. Roles of A?42/40 ratio on tau pathology are also confirmed with APP transmembrane domain (TMD) mutant hNPCs, which display differential A?42/40 ratios without mutant PS1. Moreover, naïve hNPCs co-cultured with APP TMD I45F (high A?42/40) cells, not with I47F cells (low A?42/40), develop robust tau pathology in a 3D non-cell autonomous cell culture system. These results emphasize the importance of reducing the A?42/40 ratio in AD therapy.
| S-EPMC7070004 | biostudies-literature
Project description:A variety of Alzheimer's disease (AD) mouse models overexpress mutant forms of human amyloid precursor protein (APP), producing high levels of amyloid β (Aβ) and forming plaques. However, the degree to which these models mimic spatiotemporal patterns of Aβ deposition in brains of AD patients is unknown. Here, we mapped the spatial distribution of Aβ plaques across age in three APP-overexpression mouse lines (APP/PS1, Tg2576, and hAPP-J20) using in vivo labeling with methoxy-X04, high throughput whole brain imaging, and an automated informatics pipeline. Images were acquired with high resolution serial two-photon tomography and labeled plaques were detected using custom-built segmentation algorithms. Image series were registered to the Allen Mouse Brain Common Coordinate Framework, a 3D reference atlas, enabling automated brain-wide quantification of plaque density, number, and location. In both APP/PS1 and Tg2576 mice, plaques were identified first in isocortex, followed by olfactory, hippocampal, and cortical subplate areas. In hAPP-J20 mice, plaque density was highest in hippocampal areas, followed by isocortex, with little to no involvement of olfactory or cortical subplate areas. Within the major brain divisions, distinct regions were identified with high (or low) plaque accumulation; for example, the lateral visual area within the isocortex of APP/PS1 mice had relatively higher plaque density compared with other cortical areas, while in hAPP-J20 mice, plaques were densest in the ventral retrosplenial cortex. In summary, we show how whole brain imaging of amyloid pathology in mice reveals the extent to which a given model recapitulates the regional Aβ deposition patterns described in AD.
| S-EPMC8026112 | biostudies-literature